The Human Genome Project is now on the way of elucidation of the nucleotide sequences of all the genes of our humans in a coming few years, and the genes are serving as “the design scheme of life”. It is known that the design scheme if it happens to have any damage or an acquired damage may cause diseases or aging. The progress of the Human Genome Project has enabled the understanding of many diseases including cancer at DNA level. Thus, medicine principally including diagnostics and prophylaxis will wholly make a possible innovative change. Further, the development of therapeutic treatments based on the understanding of these diseases at DNA level, namely pharmaceutical products targeting the pathologic genes and the products of the genes, has been strongly desired. However, research works linking fundamental researches to clinical researches have just started.
Cancer has also been investigated at DNA level, but anti-cancer agents for current use are mostly composed of antibiotics selected through screening, not microbial products generated by microorganisms so as to kill cancer cells. Anti-cancer agents based on the findings in the molecular biology of cancer scarcely exist. If extracellular free control of the expression of a specific intracellular gene can be achieved, the control will serve for an ultimate therapeutic therapy of cancer at gene level.
A chemical modification of DNA carrying genetic information damages the genetic information composing the fundamental base for the sustainment of viability, leading to the induction of cellular mutation and death. Additionally, it has been known that a modification via covalent bonding to the DNA in normal cell is a cause of oncogenes is, while interaction with the DNA in cancer cell can be utilized for anti-cancer agent.
The interstrand-crosslinking reaction as shown by the following formula: , which works for crosslinking the double strands of DNA, inhibits DNA replication as confirmed in various systems. It has been known that the interstrand-crosslinking reaction has far more potent actions on living organisms, compared with single-strand alkylation [S. R. Rajski and R. M. Williams, Chem. Rev., 2723-2795 (1998)].
For example, phage inactivation only requires the occurrence of interstrand-crosslinking at 1.3 equivalents on average, but the alkylation of simple single strand requires 280 equivalents of alkylation agents [P. D. Lawley, J. H. Lethbridge, P. A. Edwards, K. V. Shooter, J. Mol. Biol., 39, 181 (1969)].
Mitomycin and carzinophyllin A have been known as anti-cancer antibiotics inducing typical interstrand-crosslinking reaction. Further, numerous compounds with DNA interstrand-crosslinking actions, typically including bizelecin, have been reported so far. As representative compounds reported by far to induce DNA interstrand-crosslinking reaction, the following mitomycin, carzinophyllin A and nitrogen mustard have been known. 
Such mitomycin, nitrogen mustard (mechlorethamine) and the like are currently used as efficacious anti-cancer agents in clinical practice.
The nucleotide sequence specificities of various interstrand-crosslinking agents have been examined in detail up to now. (a) S. -J. Lee, F. C. Seaman, D. Sun, H. Xiong, R. C. Kelley, L. H. Hurley, J. Am. Chem. Soc., 119, 3434-3442 (1997); b) J. T. Millard, R. J. Spencer, P. B. Hopkins, Biochemistry, 37, 5211-5219 (1998); c) T. Fujiwara, I. Saito, H. Sugiyama, Tetrahedron Lett., 40, 315-318 (1999)). However, no correlation between the anti-cancer profiles of these compounds and the nucleotide sequence selectivities of the interstrand-crosslinking agents has yet been established. Further, no success has been made in the molecular designing of an interstrand-crosslinking compound directed for an arbitrary nucleotide sequence. Still further, the DNA interstrand-crosslinking agents synthetically prepared previously are generally at very low reaction efficiencies. For example, interstrand crosslinked products are prepared by the mustard with a known crosslinking potency of the 5′-GNC nucleotide sequence in DNA, at a yield as low as only several percents of the DNA used (Y.-H. Fan and B. Gold, J. Am. Chem. Soc., 121, 11942-11946 (1999)).
Thus, very importantly, an efficient DNA interstrand-crosslinking agent will be developed.